Post-Polio syndrome (PPS) is the most common motor neuron disease in North America. It is a clinical syndrome characterized by new weakness, fatigue, and pain. It is probably caused by a distal degeneration of enlarged motor units, occurring through axonal sprouting, as a result of the recovery process following acute paralytic polio. New weakness is likely due to permanent denervation, whereas fatigue may be due to neuromuscular junction (NMJ) transmission defects as a result of motor unit degeneration and remodeling. The normal aging process, with concomitant decreased growth hormone and insulin-like growth factor 1 (IGF-1)(which stimulate synthesis of protein and nucleic acids in muscle cells and regeneration/sprouting in peripheral nerves), are possible contributing factors. There is no specific treatment for PPS. Pyridostigmine is an anticholinesterase which inhibits the hydrolysis of acetylcholine at the NMJ and prolongs its effect. Pyridostigmine can also enhance growth hormone secretion in growth hormone deficiency states. Preliminary work indicates that: 1) NMJ transmission defects can be ameliorated with anticholinesterase agents in PPS. 2) Fatigue in PPS may be due to NMJ transmission defects, and 3) about 60% of PPS patients responded to oral pyridostigmine 180 mg/d in an open-label trial. We hypothesize that pyridostigmine will produce an amelioration of NMJ transmission in motor units and an increase in IGF-1 levels, which will result in an improvement in general health status (as assessed by the short form health survey 36, {SF-36}), in fatigue and in weakness in PPS patients. To test this hypothesis we will conduct a multicenter, randomized, double-blind, placebo-controlled treatment trial with the following objectives: 1) to assess the clinical efficacy of a 6 month course of pyridostigmine by evaluating its effect on subjective physical functioning (as measured by the SF-36 physical functional scale), on general health status (as measured by the 7 remaining sub scales of the SF-36) on subjective fatigue (as measured by the Hare fatigue scale and the fatigue severity scale), and on isometric strength (as measured by the Tufts Quantitative Neuromuscular Exam); 2) To evaluate the effect of pyridostigmine on serum IGF-1 levels; and 3) to determine the incidence and severity of side effects from pyridostigmine treatment in PPS patients. Patients will be recruited from 6 post-polio clinics in the USA and Canada. One hundred and twenty six patients will be randomly assigned to treatment with either pyridostigmine or matched placebo. There will be two baseline outcome assessments (within 4 weeks), and 3 trial assessments (after 6 weeks, 10 weeks, and six months of treatment). The primary outcome measure for the study will be the change in physical functioning as assessed by the SF-36 at baseline and after 6 months of treatment. This trial may result in the identification of a safe and effective treatment for PPS.